Ash 2021 – Agios and Forma take different paths in sickle cell disease

Forma still hopes for accelerated approval of etavopivat, while Agios believes that taking its time with mitapivat will pay off.

Agios and Forma are neck and neck in a race to develop an oral pyruvate kinase R activator for sickle cell disease, but the latter is hoping to pull ahead. Despite recently admitting that the FDA needs data beyond haemoglobin response alone, Forma still believes that an accelerated approval is possible, executives at the Ash meeting told Evaluate Vantage.

Meanwhile, Agios reckons the traditional, full approval route is the way to go. And that group’s chief medical officer, Sarah Gheuens, was scathing about the notion that the FDA might allow a quick path to market. “We’re not the first drug to market that improves haemoglobin. [Global Blood’s] Oxbryta was first. Therefore, every drug that does something similar has a higher hurdle to climb.”

Oxybryta got FDA accelerated approval in 2019, after 51% of patients achieved a haemoglobin response, defined as an increase of 1g/dl or more versus baseline, in the pivotal Hope trial. A confirmatory study, Hope Kids 2, is ongoing.

Mitapivat vs etavopivat

This year’s Ash saw data from both Agios and Forma in sickle cell disease, with mitapivat and etavopivat respectively.

The results largely reaffirm the conclusion drawn at Ash 2020, which featured earlier data cuts from the same studies: Forma’s compound appears to have a slight edge on efficacy, with the usual caveats about cross-trial comparisons (Ash 2020 – Forma gets an early edge over Agios in sickle cell disease, December 7, 2020).

Cross-trial comparison of PKR activators in sickle cell disease
Project Etavopivat (FT-4202; Forma) Mitapivat (Agios)
Trial Ph1 (NCT03815695), 12-wk open-label portion Ph1 (NCT04000165)*
% haemoglobin responders 73% (11/15) 56% (9/16)
Increase from baseline in Hb 1.5g/dl (mean) 1.2g/dl (mean)**
Total VOCs 3 4
On-treatment VOCs 1 2^
Haemoglobin response defined as haemoglobin increase of ≥1.0g/dl from baseline. *NIH-sponsored trial; **50mg bid dose; ^Both VOCs occurred during dose taper phase. Source: Ash & company presentations.

With both compounds, there remain concerns about vaso-occlusive crises (VOCs), painful events that occur in sickle cell disease. These worries led to drops in Agios and Forma’s share prices when the Ash abstracts were released.

However, both groups believe that the VOCs seen in their trials were down to the patients’ underlying disease rather than the PKR activators.

“We never claimed to be a full cure,” said Agios’s Ms Gheuens. “We’re trying to provide a reduction – that doesn’t mean you’re going to see an absence.”

Indeed, Forma highlighted an analysis showing that the annualised rate of VOCs dropped to 0.3 during the 12-week open-label portion of its trial versus an annualised rate of 0.93 in these subjects before the trial began.

To complicate matters further, both studies included four-week follow-up periods, during which patients did not receive the project in question. And several of the VOCs happened during these windows – something that Forma’s chief medical officer, Patrick Kelly, put down to drug withdrawal.

Accelerated vs full

Still, Ms Gheuens admitted: “Honestly, I think these worries in the investor community will remain until we present the full dataset of Rise-Up,” referring to Agios’s phase 2/3 trial in sickle cell.

The phase 3 section of this study has two co-primary endpoints: haemoglobin response and annualised rate of sickle cell crises, both at one year. Agios hopes to get full approval for mitapivat in sickle cell disease in 2026.

Forma has the traditional pathway to fall back on. To this end, the group’s pivotal study, Hibiscus, also has co-primary endpoints of haemoglobin response at six months and annualised vaso-occlusive crises at one year, which would support full approval.

But the group is still holding out hope for accelerated approval. “There’s no guarantee for accelerated review, but we think it’s a worthwhile effort to pursue that, because it means we’ll be able to deliver this to patients perhaps a year earlier than via the traditional path,” its chief executive, Frank Lee, told Vantage.

Still, hopes for this outcome dimmed during Forma’s third-quarter results, when the group said that the FDA had asked for data to support haemoglobin response as a surrogate endpoint. It is unclear yet what these additional data might be.

Ms Gheuens, although confident that Agios is doing the right thing, ultimately believes that "there is easily room for two PK activators in context of sickle cell disease". If the traditional approval path is the way this plays out, it could be some time before this is put to the test.

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